One of the most well-known and widely used classes of antibacterial agents is the class known as the .beta.-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (.beta.-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the .beta.-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given .beta.-lactam antibiotic results because the microorganism produces a .beta.-lactamse. The latter substances are enzymes which cleave the .beta.-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit .beta.-lactamases, and when a .beta.-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a .beta.-lactamase inhibiting substance and a .beta.-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.
This invention relates to 6-aminopenicillanic acid 1,1-dioxide, a new .beta.-lactamase inhibitor, esters thereof readily hydrolyzable in vivo, and salts of these compounds; and also derivatives of 6-aminopenicillanic acid 1,1-dioxide having a carboxy protecting group. Said latter compounds are useful as chemical intermediates for 6-aminopenicillanic acid 1,1-dioxide and esters thereof.
In Volume 76 (January to June 1972) of the Chemical Substances Index of Chemical Abstracts, there appears an entry under the heading "4-thia-1-aza-bicyclo[3.2.0]-heptane-2-carboxylic acid, 6-amino-3,3-dimethyl-7-oxo,4,4-dioxide." This latter name is, of course, an alternate name for 6-aminopenicillanic acid 1,1-dioxide. The Index refers to Abstract No. 153735n, which is an abstract of West German Offenlegungsschrift No. 2,140,119. However, Abstract No. 153735n makes no reference to any penicillin 1,1-dioxides. West German Offenlegungsschrift No. 2,140,119 discloses a new process for oxidizing penicillin derivatives (e.g. 6-aminopenicillanic acid) to the corresponding 1-oxide. It is stated that the latter process produces penicillin 1-oxides (e.g. 6-aminopenicillanic acid 1-oxide) uncontaminated by the corresponding 1,1-dioxides (e.g. 6-aminopenicillanic acid 1,1-dioxide). No other mention of penicillin 1,1-dioxides is made in West German Offenlegungsschrift No. 2,140,119.
1,1-Dioxides of benzylpenicillin, phenoxymethylpenicillin and certain esters thereof have been disclosed in U.S. Pat. Nos. 3,197,466 and 3,536,698, and in an article by Guddal et al., Tetrahedron Letters, No. 9, 381 (1962). Harrison et al., in the Journal of the Chemical Society (London), Perkin I, 1772 (1976), have disclosed a variety of penicillin 1,1-dioxides, including methyl phthalimidopenicillanate 1,1-dioxide and methyl 6,6-dibromopenicillanate 1,1-dioxide. U.S. Pat. No. 3,544,581 discloses 6-aminopenicillanic acid 1-oxide. Chaikovskaya et al., Antibiotiki, 13, 155 (1968), disclose that benzyl penicillin 1,1-dioxide was found to be inactive when tested for .beta.-lactamase inhibiting activity against E. coli.
West German Offenlegungsschrift No. 2,824,535, published Dec. 14, 1978, and Iranian Pat. No. 19,601, granted July 12, 1978, disclose penicillanic acid 1,1-dioxide, and esters thereof readily hydrolyzable in vivo, as antibacterial agents and as .beta.-lactamase inhibitors. Penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo increase the antibacterial effectiveness of certain penicillin and cephalosporin compounds against certain bacteria.